Fetuin-A interferes with insulin action in animal studies, but data on fetuin-A and diabetes risk in humans are sparse and the role of nonalcoholic fatty liver disease in this association is unknown. From 2000 to 2006, we prospectively identified 470 matched incident diabetes case-control pairs in the Nurses’ Health Study, for whom levels of plasma fetuin-A, alanine transaminase (ALT), and γ-glutamyltranspeptidase (GGT) were measured. After multivariate adjustment for covariates, including ALT and GGT, the odds ratio (OR) (95% CI) comparing extreme fetuin-A quintiles was 1.81 (1.07–3.06) (P for trend = 0.009). A mediational analysis showed that this positive association was largely (79.9%) explained by fasting insulin and hemoglobin A1c levels; after further adjustment of these factors, the OR (95% CI) comparing extreme quintiles was attenuated to 1.09 (0.56–2.10) (P for trend = 0.42). In addition, liver enzymes did not modify this association (P for interaction = 0.91 for ALT and 0.58 for GGT). When results from this study were pooled with those in three prior prospective investigations of the same association, a consistent, positive association was observed between high fetuin-A levels and diabetes risk: the relative risk (95% CI) comparing high versus low fetuin-A levels was 1.69 (1.39–2.05) (P for heterogeneity = 0.45). These findings suggest that plasma fetuin-A levels were independently associated with higher risk of developing type 2 diabetes.